Diminazene aceturate is one of a limited number of drugs currently being used in animals to treat the tsetse fly-transmitted protozoal disease, African trypanosomiasis. Efficacy of the drug at the recommended single IM administered doses of 3.5 and 7.0 mg/kg of body weight is widely acknowledged. However, resistance to the drug at these dosages has been reported. Although the mechanisms of resistance to diminazene are poorly understood, field and experimental data indicate that it may develop naturally through administration of subcurative doses, or as a result of cross-resistance. Evidence from other experimental studies indicates that there are additional mechanisms by which trypanosomes may develop resistance to diminazene aceturate. For instance, some populations ot Trypanosoma brucei and T. vivax are refractory to treatment because of their ability to invade the CNS, a site that is believed to be poorly accessible to diminazene. Furthermore, in recent studies carried out in goats, it has been documented that the ability of T. Congolense IL 3274 to survive treatment with diminazene depends on the stage of infection when treatment is administered; populations of the parasite reappeared in animals that were treated on day 19 after tsetse fly challenge, whereas all goats were cured when treated on day 1 of infection. Because trypanosomes are confined to the skin on day 1 after infection, but thereafter invade the blood circulation, it is possible that the efficacy of the treatment on day 1 is attributable to exposure of the small number of parasites, relative to later stages of infection, to higher concentrations of drug than those attained in blood. The objective of the study reported here was to determine whether diminazene's pharmacokinetics differ between plasma and lymph draining the skin of goats and therefore account for the variation in therapeutic activity of the drug at different stages of a tsetse fly-transmitted infection. Peripheral lymph was used for this work because it appears to be identical in composition to tissue interstitial fluid, into which trypanosomes are inoculated by infected tsetse flies when feeding.

Objective--To study whether end products of 2 pathways of anaerobic energy metabolism, lactate and purines, that accumulate in the blood after intense exercise indicate any relation to exercise performance. Design--Venous blood samples were taken within 1 and 15 minutes after a trotting race of 2,100 m. Animals--16 Clinically healthy Standardbred trotters. Procedure--Blood and plasma lactate concentrations were measured by enzymatic analyzer, and purines, uric acid and allantoin, were determined by high-performance liquid chromatography. The concentrations of metabolites were then correlated to racing time and individual performance indexes that are annually calculated from the percentage of winnings, placings, and starts rejected, average earnings per start, and the racing record. Results--Blood lactate concentration immediately and calculated cell lactate concentration immediately and 15 minutes after the race correlated positively (P < 0.05 to P < 0.01 ) with the individual performance indexes. Plasma lactate concentration was not correlated to the individual performance indexes. Uric acid concentration, immediately and 15 minutes after the race, was negatively correlated (P < 0.05) to the individual performance indexes, and a positive relation (P < 0.05) was found between the highest concentration of uric acid and the racing time. Concentration of allantoin immediately or 15 minutes after the race did not have any significant correlation to the individual performance indexes. Conclusions--Accumulation of lactate in the blood, which was greater in the superior performing horses, may prove to be an useful predictor of anaerobic capacity. The results also indicate that the loss of purine nucleotides was less in the superior performing horses, although further studies are needed to confirm this.

Duration and magnitude of hypothalamic-pituitary-adrenal axis suppression caused by daily oral administration of a glucocorticoid was investigated, using an anti-inflammatory dose of prednisone. Twelve healthy adult male dogs were given prednisone orally for 35 days (0.55 mg/kg of body weight, q 12 h), and a control group of 6 dogs was given gelatin capsule vehicle. Plasma cortisol (baseline and 2-hour post-ACTH administration) and plasma ACTH and cortisol (baseline and 30-minutes post corticotropin-releasing hormone [CRH] administration) concentrations were monitored biweekly during and after the 35-day treatment period. Baseline plasma ACTH and cortisol and post-ACTH plasma cortisol concentrations were significantly (P < 0.05) reduced in treated vs control dogs after 14 days of oral prednisone administration. By day 28, baseline ACTH and cortisol concentrations remained significantly (P < 0.05) reduced and reserve function was markedly (P < 0.0001) reduced as evidenced by mean post-CRH ACTH, post-CRH cortisol, and post-ACTH cortisol concentrations in treated vs control dogs. Two weeks after termination of daily prednisone administration, significant difference between group means was not evident in baseline ACTH or cortisol values, post-CRH ACTH or cortisol values, or post-ACTH cortisol values, compared with values in controls. Results indicate complete hypothalamic-pituitary-adrenal axis recovery 2 weeks after oral administration of an anti-inflammatory regimen of prednisone given daily for 5 weeks.

Canine erythrocytes were loaded with the antineoplastic drug doxorubicin and then treated with 0.16% glutaraldehyde. This procedure has been previously shown to slow down the efflux of doxorubicin from erythrocytes and to result in the selective targeting of the carrier erythrocytes to liver. Three dogs were treated each with 2 different schedules of IV bolus administration of doxorubicin (0.4 mg/kg of body weight): free drug and doxorubicin encapsulated in glutaraldehyde-treated erythrocytes. The 2 treatments yielded consistent differences in the plasma pharmacokinetic properties of doxorubicin and of its only metabolite, doxorubicinol. A triphasic exponential decay of doxorubicin plasma concentrations was observed on injection of the free drug. Conversely, in the case of erythrocyte-encapsulated doxorubicin, 4 phases of plasma concentrations of doxorubicin were found. The plasma concentrations of doxorubicinol, after a steady increase during the first hour, followed patterns of decay comparable to those of the parent drug. On the basis of the kinetic variables calculated with the 2 administration schedules, area under curve concentrations of plasma doxorubicin were 136 microgram.h/L (free infusion) and 734 microgram.h/L erythrocyte-encapsulated drug). Significant alterations of hematologic and hematochemical factors were not observed in the 3 dogs during and after the 2 treatments. On the basis of our findings, doxorubicin-loaded and glutaraldehyde-treated erythrocytes may potentially be used in the treatment of systemic and hepatic tumors in dogs.

Oxytetracycline (OTC) pharmacokinetic values in plasma and bile were ascertained after IV administration of the drug. At 6 hours after administration of 1 mg of OTC/kg of body weight, 2.15% of the dose was found in the bile and 37.6% was found in the urine. At 2 hours after administration, the peak bile-to-plasma OTC concentration ratio was 60:1. Bioavailability of OTC was 47.6% when it was administered orally to fasted turkeys and was 9.4% when administered to fed turkeys.

Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg, IV), and antipyrine (35 mg/kg, IV) were studied in adult female dwarf goats (n = 5) before and after implantation with trenbolone acetate (5 mg/kg). Pretreatment with trenbolone caused a significant decrease in the elimination rate of the drugs tested: for sulfamethazine, 5 times; for antipyrine, 3 times; and for trimethoprim, 2 times. After treatment with testosterone (1 mg/kg, SC, twice weekly for 2.5 weeks), female goats (n = 5) had a similar decrease in the elimination rate of sulfamethazine. Other induced effects included a change in social behavior, a lower voice, and the development of a typical billy goat-like odor. Plasma creatinine concentrations after androgen administration were significantly higher than those before androgen administration; changes were not observed in plasma urea values. Because of the differences observed, we believe that more attention should be paid to the effects of androgenic agents on drug kinetic properties, with particular reference to studies on clinical efficacy, side effects, and drug residues in food products.

Hyperxanthinuria and xanthine uroliths have been recognized with increased frequency in dogs with ammonium urate uroliths that had been given allopurinol. We hypothesized that dietary modification might reduce the magnitude of uric acid and xanthine excretion in urine of dogs given allopurinol. To test this hypothesis, excretion of metabolites, volume, and pH were determined in 24-hour urine samples produced by 6 healthy Beagles during periods of allopurinol administration (15 mg/kg of body weight, PO, q 12 h) and consumption of 2 special purpose diets: a 10.4% protein (dry matter), casein-based diet and a 31.4% protein (dry matter), meat-based diet. Significantly lower values of uric acid (P = 0.004), xanthine (P = 0.003), ammonia (P = 0.0002), net acid (P = 0.0001), titratable acid (P 0.0002), and creatinine (P = 0.01) excreted during a 24-hour period were detected when dogs consumed the casein-based diet and were given allopurinol, compared with the 24-hour period when the same dogs consumed the meat-based diet and were given allopurinol. For the same 24-hour period, urine pH values, urine volumes, and urine bicarbonate values were significantly (P = 0.0004, P 0.04, and P = 0.002, respectively) higher during the period when the dogs were fed the casein-based diet and given allopurinol than when they were fed the meat-based diet and given allopurinol. Endogenous creatinine clearance was significantly (P = 0.006) lower when dogs were fed the casein-based diet and given allopurinol than when they were fed the meat-based diet and given allopurinol. Significantly lower concentrations of plasma uric acid (P 0.0001), plasma xanthine (P = 0.01), and serum urea nitrogen (P = 0.0001) were detected when dogs consumed the casein-based diet and were given allopurinol than when they consumed the meat-based diet and were given allopurinol.

Adrenocortical function was assessed in 27 Beagle pups at 2, 4, 6, 8, 10, and 12 weeks of age by determination of plasma sodium, potassium, and chloride concentrations; serum aldosterone and cortisol concentrations; and plasma ACTH concentrations. Serum cortisol concentration was measured before and 1 and 2 hours after IM administration of 2.2 IU of ACTH/kg of body weight. Serum progesterone concentration also was determined for all pups at 2, 4, and 6 weeks of age. Mean baseline cortisol concentration was lower for pups 8 weeks old or younger than for mature dogs. Nevertheless, mean serum ACTH-stimulated cortisol concentration in dogs of all age groups increased into the adult reference range after administration of ACTH. For pups 4 weeks old or younger, increase in cortisol concentration was maximal at 2 hours after ACTH administration. However, in pups between 6 and 12 weeks of age, the increase in cortisol concentration was maximal 1 hour after ACTH administration in about a third of the pups, whereas the remaining pups had peak values at 2 hours. Mean plasma sodium, potassium, and chloride concentrations for each age group were within the reference ranges established for mature dogs, with the exception of lower mean plasma sodium and chloride concentrations in pups 4 weeks old or younger. Mean serum aldosterone concentration in pups of each age group was substantially higher than the range of aldosterone concentrations for clinically normal mature dogs. Median progesterone concentration was uniformly less than 0.2 ng/ml for all pups 6 weeks old or younger. The normal endogenous ACTH concentration and adequate cortisol responses to exogenous ACTH seen in our pups would support functional pituitary gland and adrenal cortex for cortisol production. The low baseline cortisol concentration observed in the pups of this study may be related to reduced binding of cortisol to plasma proteins, as exists in human infants.

Plasma insulin concentration of many species has a characteristic early or acute-phase response in the minutes after IV administration of glucose, However, the plasma insulin response of horses soon after the Iv administration of glucose has not been examined, whereas the more prolonged response has been evaluated. We examined the plasma insulin and glucose concentration responses of adult mares during the 30 minutes after rapid Iv administration of glucose (0.33 g/kg of body weight). Plasma glucose concentration peaked at 664 +/- 54 mg/dl within I minute of cessation of glucose administration, whereas insulin concentration peaked at 326 +/- 24 pmol/L at 2 minutes after the end of glucose administration. Thus, these mares had an acute insulin response, consistent with that observed in other species, including dogs, human beings, and cattle.

Because hepatocyte-stimulating factor/interleukin 6 (IL-6) the principal inducer of acute-phase protein synthesis in the liver, quantification of its activity in blood provides an early and sensitive assessment of the acute-phase response. Circulating IL-6 activity was monitored in 4 adult horses for 72 hours after IV administration of endotoxin. In 4 experiments performed at weekly intervals and in randomized order, each horse was given endotoxin-1,000, 30, 1, and 0 ng/kg of body weight. Plasma IL-6 activity was quantified as the ability to promote growth of the IL-6-dependent B-cell hybridoma, B13.29 clone B9. Interleukin-6 activity (171 +/- 10.2 U/ml) was found in all pretreatment plasma samples and was significantly (P < 0.05) increased above baseline from 2 to 12 hours after 1,000 ng of endotoxin/kg was given and at 3 hours after 30 ng of endotoxin/kg was given. After 1,000- or 30-ng/kg dosage of endotoxin, peak plasma IL-6 activity (10,128 +/- 4,096 and 1,555 +/- 1,326 U/ml, respectively) was observed for 3 hours. The IL-6 response of endotoxin-treated horses began about 1 hour after tumor necrosis factor appeared in the circulation, and its course closely approximated the endotoxin-induced febrile reaction. Significant increase in plasma IL-6 activity was not detected in horses given 1 ng of endotoxin/kg or control buffer.